For humans, frailty constitutes of one of the most prominent and consistent features of aging and represents the summation of the effects of muscle atrophy and weakness. For the elderly, physical frailty contributes to impaired mobility, a high risk of falling, an increased incidence of muscle injury, and a decreased quality of life. Despite considerable effort over the past decade, little progress has been made in lessening the magnitude of the problem. During our first five years of support, research on a dozen or more varieties of knockout and transgenic mice, this Program Project identified the Sodl^' mouse as a highly promising model to test the working hypothesis of Project 1 that age-related skeletal muscle atrophy results from a decrease in the total number of motor units caused by increased superoxide-mediated oxidative stress in neurons and muscles, such that: (i) oxidative stress in neurons initiates a loss of motor neurons, impairs axonal sprouting from surviving motor neurons, and inhibits nerve regeneration; and (ii) oxidative stress in muscles fibers inhibits reinnervation and contributes to decreased contractility of innervated muscle fibers. The working hypothesis will be tested through experiments on SodfA and Sod1+/+ mice, transgenic Socf7v" mice with Sod1 expression rescued only in nerves (Soc/fA(N+) mice) or muscles (Soc(7~/~(M+) mice), and tissue-specific knockout mice that lack CuZnSOD activity only in nerves (Sod1A3,4N)N) or muscles (Sod 1 A3,4^). These models allow us to test hypotheses regarding the contribution of systemic oxidative stress, as well as tissue-specific oxidative stress on the structure and function of motor nerves, muscles, motor units and muscle fibers. Genetically modified mice will be studied at 6-8 months and 18-20 months, whereas Sod1+/+ mice will be studied at 6-8, 18-20, and 28-30 months. Unique aspects of the proposed studies are the determination of motor unit properties and contractility of permeabilized single fibers from Soc/f/"mice,, null mice with tissue-specific rescue, and tissue-specific Sodl knockout mice. Furthermore, studies of the relative timing of changes in nerves and muscles that have not been undertaken previously in the same animals will be particularly illuminating for establishing cause-effect relationships of age-related changes in the neuromuscular system. Along with Projects 2 and 3, studies utilizing the very powerful mouse models listed above will determine the mechanistic role of superoxide-induced oxidative stress in muscles and nerves in age-related skeletal muscle atrophy. The Public Health significance is the necessity to understand the mechanisms underlying age-associated skeletal muscle atrophy and weakness to provide the basis for health professionals to design and implement scientifically based strategies to ensure 'successful aging' by reducing and perhaps even eliminating physical frailty in the elderly population.